Esters of penicillin s-dioxide



Patented Sept. 27, 1949 UNITED STATES PATENT OFFICE ESTERS OF PENICILLINS-DIOXIDE Edward F. Rogers, Middletown, and Karl Folkers, Plainfield, N.J., assignors to Merck & 00., Inc., Rahway, N. J., a corporation of NewJersey No Drawing. Application April 19, 1946, Serial No. 663,621

wherein R. represents lower alkyl and aralkyl substituents. Lower alkylradicals include methyl, ethyl, propyl, etc. and aralkyl includes suchcompounds as benzyl (--CH2CsI-I5) R1 represents benzyl and substitutedbenzyl substituents. By the term substituted benzyl compounds is meantcompounds having the formula wherein X is alkoxy, halogen.

It has now been discovered in accordance with the present invention thatcompounds represented by the above formula can be prepared by oxidizingcompounds of the general formula acyloxy, hydroxy and 2 Serial No.636,256, filed December 20, 1945, now abandoned.

In accordance with a preferred embodiment of the present invention, theoxidation is accomplished b buffering an organic solvent solution ofcompounds represented by Formula II to neutrality, reacting the neutralsolution with potassium permanganate at room temperature, reducing anyexcess potassium permanganate present with a reducing agent, such assulfur dioxide, and recovering compounds represented by Formula I.

Our invention and the new compounds with which it is concerned, will beapparent from the following illustrative example:

Example About 116 mg. of methyl penicillin G (represented by Formula IIwherein R. is a methyl substituent and R1 is a benzyl substituent) weredissolved in 10 ml. of dioxane. The pH of the solution was adjusted to6.8 by the addition of 5 ml. of 1.7 M phosphate buffer. 3.6 ml. of 3.88%potassium permanganate solution were added and the mixture was stirredfor one hour at 25 C. Sulfur dioxide was then added until thepermanganate color was discharged. The solution was concentrated toapproximately one quarter of the initial volume at room temperature andthen extracted with three equal volumes of chloroform. Evaporation ofthe chloroform in vacuo resulted in a residue which crystallized on theaddition of ether. This material, methyl penicillin- G S-dioxide, had amelting point of 173-174" C. During the melting point determination aslight softening of the crystals was noted at ISO- C. Uponrecrystallization from chloroform-ether, crystals of irregular plateswere obtained. These crystals melted with decomposition at 173-174. C.,and had an optical rotation of (00 +172 when measured in an 0.8%chloroform solution and +192 when measured in a 1.0% dioxane solution.The esters of penicillin G. S -dioxide have 10-20% of the activity ofpenicillin and are much more stable than penicillin in acid solution.This adapts the new compounds for oral or topical medication where acidconditions normally prevail.

Various changes and modifications of our invention as described abovemay be made which would still be within the scope thereof. Accordingly,such changes and modifications, to the extent that they are within thepurview of the appended claims are to be regarded as part of ourinvention.

3 We claim: 5. The process that comprises buflerlng an 1. A compound ofthe formula organic solvent solution of compounds of the g formula\GCH-COOR H10 41 5 \OGHCOOR H 0 0 fl mo t N H-C=0 0E NHCOCH2COHB whereinR is selected from the group consisting IVE-0 (Pam-Cuffs of lower alkyland aralkyl.

2. A compound of the formula wherein R represents a lower alkylsubstituent HC to neutrality, reacting the neutral solution withpotassium permanganate, reducing any excess potassium permanganate withsulfur dioxide and H16 0\, /N recovering compounds of the formula CH(En-o-o 20 CCHOOOR NH-CO-CHr-CaHs H I wherein R represents a lower alkylsubstituent. 3

3. Methyl penicillin-G. S-dioxide having a C melting point ofapproximately 173474 0., an on o=o optical rotation of approximately (a)+172 25 when measured in 0.8% chloroform solution, an optical rotationof approximately +192 wherein R is as above when measured in 1.0%dioxane solution and The process that comprises buffering to havmg thefollowmg Structural formula neutrality an organic solvent solution ofmethyl H3C\ 3 penicillin G having the formula o es-4:00am

/A E m0 0, N

\ fi JGH-COOCH3 1 0 O H30 s\ /N on NH-C OCHaCaH6 H C O 4. The processthat comprises buffering to neutrality an organic solvent solution of acom MPG (FCHTQH d h formul poun of t e a and reacting the neutralsolution with potassium permanganate to form methyl penicillin G.

/(|:-(|3H-000R S-dioxide having the formula H3O s N H c Cg a o-o c |t 'HOOCH; NH-C OCHzCaH5 Hi0 N wherein R is selected from the groupconsisting of lower alkyl and aralkyl, reacting the neutral CH-C=Osolution with potassium permanganate redm- LT mg any excess potassiumpermanganate with sulfur dioxide and recovering a compound of the EDWARDR ROGERS. formula KARL FOLKERS.

CH COOR REFERENCES CITED g t The following references are of record inthe file of this patent:

Abraham: British Journal of Experimental Pathology, vol. 23, June 1942,No. 3, page 112. (PCBPQH Squibb Institute for Medical ResearchMonthwherein R is as above. 1y Progress Report for April 1944, SX IV,page 5.

